. Long-term objectives are to: (1) develop and market novel magainin peptide drugs to treat C. difficile-related pseudomembranous colitis, for which current therapy is unsatisfactory; and (2) advance the knowledge and therapeutic potential of ion channel-forming peptide drugs. Methodology includes in vitro structure activity studies to design magainin drugs with maximum narrow spectrum activity against C. difficile, which resist gastrointestinal proteolytic enzymes, and do not induce resistance development. The most active compounds developed by structure activity relationship studies will also be tested for synergy with the leading drugs against C. difficile. The most active compounds and synergistic combinations will be tested in the in vivo hamster model. Those with greatest in vivo efficacy will be formulated for oral delivery; and stability, pathology, and toxicology studies will be performed. This project may yield important gastrointestinal drugs with improved potency against C. difficile and excellent market potential. It will also advance the fields of peptide antibiotics and host defense therapy.